Patricia Goldman-Rakic, PhD - US grants

The frontal lobes reach their highest development in man, in whom they are thought to provide the neural basis for the analysis of past and future actions, the programming of sequential behaviors toward long-range goals, and the regulation of socially and culturally appropriate behavior. The ultimate goal of this research program is to understand the frontal lobes and their contribution to higher-order cognitive functions by detailed experimental study of its anatomy, physiology, neurochemistry and behavioral expression in nonhuman primates. The same studies should provide a neurobiological basis for understanding a variety of behavioral disorders that reflect disease in the frontal cortex and anatomically related structures such as the basal ganglia and basal forebrain. This program has evolved during the last decade to its present focus on: (1) anatomical organization with particular emphasis on microstructural analysis of the topographic, laminar and columnar organization, and degree of collateralization of prefrontal cortical connections using advanced neuroanatomical tracing techniques including autoradiography, fluorescent tracers, and horseradish peroxidase histochemistry; (2) neurochemical organization of prefrontal pathways including neurotransmitters, enzymes and receptors using immunohistochemistry, electron microscopy, and receptor autoradiography; (3) functional analysis of prefrontal cortex using lesion behavioral analysis, 2-deoxyglucose autoradiography for mapping metabolic activity and electrophysiology alone or in combination with anatomical methods; and (4) comparative and life-span developmental studies to establish a link between studies of prefrontal cortex in nonhuman primates and in man by analysis of a variety of behaviors common to both species. All experiments are conducted on rhesus monkeys whose association cortex including the prefrontal cortex is well developed and who are unexcelled laboratory animal models for the study of cortical function. By design, our strategy is multidisciplinary, but each project intersects with every other, both conceptually and technically. The proposed studies should enrich our understanding of the neural circuits and cellular basis of cognitive functions and their breakdown in mental disease.

The frontal lobes reach their highest development in man, in whom they are thought to provide a sophisticated nueral system for the analysis of options and outcomes, organization of behavior toward future goals, and for the regulation of socially and culturally appropriate behavior. The ultimate goal of this research program is to understand the frontal lobes and their contribution to higher-order cognitive functions by detailed experimental study of its anatomy, physiology, neurochemistry and behavioral expression in nonhuman primates. This program has evolved over a period of more than 15 years to its present focus on: [1] anatomical organization with particular emphasis on microstructural analysis of the topographic, laminar and columnar organization, and degree of collateralization of prefrontal cortical connections using advanced morphological techniques including autoradiography, horseradish peroxidase, fluorescent dyes, fluorescent histochemistry, immunohistochemistry, electron microscopy, and receptor autoradiography; [2] functional analysis of prefrontal cortex using a combination of behavioral analysis, 2-deoxyglucose autoradiography for mapping metabolic activity and electrophysiology to elucidate the cellular basis of prefrontal function; [3] psychopharmacological and comparative studies to study the role of monoamines in cognitive functions and to establish a link between studies of prefrontal corte in nonhuman primates and in man, e.g., by analysis of behaviors common to both species; and also assessment and drug treatment of cognitive deficits in aged animals with endogenous depletion of prefrontal catecholamines; and [4] studies of development and plasticity of prefrontal neural connectivity and its relation to recovery of function after early brain injury. All experiments are conducted on rhesus monkeys whose prefrontal corte is well developed and who are unexcelled as laboratory animal models of human learning and memory. This research strategy is broadly multidisciplinary and each major project intersects with every other, both conceptually and technically. The proposed studies should enrich our understanding of the neural circuits and cellular basis of cognitive functions and their breakdown in mental disease.

This Center is composed of five projects involving investigators at four institutions all committed to understanding the neurochemical basis of normal cognition and its dissolution in schizophrenia. Unraveling the cortical mechanisms which mediate the complex cognitive functions of the prefrontal cortex is considered an essential step in achieving this understanding. This Center is unified by the hypothesis that neurotransmitter dysregulation may produce compromised cortical architecture ("reduced neuropil") and is a primary feature of cortical functional disturbance in particularly dopamine (DA), in the regulation of excitatory neurotransmission in the circuitry of working memory. Project 1 examines the role of dopaminergic (and serotonergic) modulation of NMDA and non-NMDA receptors in working memory circuits in vivo. Project 2 introduces a potentially powerful new approach to neuropathology, the fixed-slice preparation to study dendritic morphology and cortical circuitry involving dopamine (and serotonin) in postmortem brain and a "living-then-fixed" preparation to test the hypothesis that dopamine alters dendritic morphology in prefrontal regions of non-human primate models of DA dysregulation produced in Project 3. Project 3 involves the study of non-human primate models produced by chronic (and acute)PCP and chronic AMPH sensitization which our findings indicate result in DA dysregulation; working memory, smooth pursuit eye tracking and neurochemical effects of chronic treatments will be investigated. Project 4 examines the degree of DA dysregulation in schizophrenia by measuring DA turnover and D2 receptor density in cortex and the striatum of schizophrenic patients using SPECT imaging to test the hypothesis that low basal levels of DA predispose to high phasic response. Project 5 is a coordinated study in normal monkeys, normal humans and patients with schizophrenia designed to test the novel hypothesis that reduction in glutamatergic neurotransmission has therapeutic potential in the treatment of schizophrenia. The collective results from these projects will illuminate our understanding of the interactions between DA and its cellular and subcellular targets in prefrontal cortex and establish the role of dopamine dysregulation in the etiology, pathophysiology, and neuropathology of schizophrenia.

This is a competing renewal to study the structure and function of the prefrontal cortex in nonhuman primates. The proposed research has the long- range goal of understanding cognitive processes in the human brain through animal models. Its focus is on the principal sulcus (PS) (Walkers'area 46) of the macaque dorsolateral prefrontal cortex; this region of the primate cortex is essential for the process of working memory. Our specific goal in this grant is to provide a neurobiological foundation for understanding the memory functions of the PS at the areal, network, column and single cell levels. A series of anatomical studies will combine pathway tracing and electrophysiology and, in some instances immunocytochemistry, to examine selected visual, motor and intrinsic connections of prefrontal columns upon which memory functions are mapped. In complementary studies, a battery of functional approaches, e.g. intracortical injections of bicucculine for temporary disruption of function (Specific Aim #2), single- and double-label 2-deoxyglucose (Specific Aims #3 and #4) and finally single cell recording studies (Specific Aim #5) conducted in animals trained to perform memory-guided and sensory-guided oculomotor delayed response tasks are designed to provide a comprehensive analysis of the topography and dynamics of working memory in prefrontal cortex. These studies will also test the hypothesis that areas anatomically interconnected with the PS and parietal cortex are likewise dedicated to spatial cognition, each making a distinctive contribution within a distributed network defined by circuitry. The 2-deoxyglucose metabolic mapping technique allows visualization of metabolic activity in all areas of the brain during a given behavioral condition; and the double-label version of this method, developed in this laboratory, can address the long-standing issue of the cortical column as the functional unit of the cerebral cortex by examining the same cortical columns under two behavioral conditions in the very same animal. The columnar basis of working memory at the cellular level will be addressed by combined anatomical tracing and single cell recording studies. The proposed studies should advance our understanding of the circuit and cellular basis of cognitive functions and their breakdown in mental disease.

This is a request for renewal of an RSA. The purpose of my research is to enhance the understanding of cognitive processes in the human brain through behavioral, anatomical, and physiological studies in nonhuman primates. The main focus is on the principal sulcus (PS) (Walkers'area 46) of the macaque dorsolateral prefrontal cortex; this region of the primate cortex is essential for the process of working memory, which underlies a wide range of cognitive processes in humans including comprehension, reasoning, and planning for the future. The specific plan for the next five years is to continue neurobiological studies of the spatial memory functions of the PS at the areal, network, column and single cell levels. A series of anatomical studies will combine pathway tracing and electrophysiology and, in some instances immunocytochemistry, to examine selected visual, motor and intrinsic connections of prefrontal columns upon which memory functions are mapped (Specific Aim #1). In complementary studies, a battery of functional approaches, e.g., intracortical injections of bicucculine for temporary disruption of function (Specific Aim #2), single- and double-label 2-deoxyglucose (Specific Aims #3 and #4) and finally single cell recording studies (Specific Aim #5) will be conducted in animals trained to perform memory-guided and sensory-guided oculomotor delayed response tasks. These studies are designed to provide a comprehensive analysis of the topography and dynamics of working memory in prefrontal cortex and a test of the hypothesis that areas anatomically interconnected with the PS are dedicated to spatial cognition, each making a distinctive contribution. In addition, the RSA supported studies on nonhuman primates have implications for understanding the causes and symptoms of schizophrenia, the mental disease in which frontal lobe dysfunction is most prominent. Through my role as P.I.. of an NIMH funded Center for Neuroscience Research in Schizophrenia, I will be engaged directly in immunocytochemical, cytological, and receptor autoradiographic studies of schizophrenic cortex and, in general, the Center will develop primate models by manipulating cortical development in utero and also by lesion and drug induction of symptoms such as deficits in predictive eye tracking, memory and perseverative behavior. The proposed studies should advance our understanding of the circuit and cellular basis of cognitive functions, their development in ontogeny and their dissolution in mental disease.

This is a request for renewal of an RSA. The purpose of my research is to enhance the understanding of cognitive processes in the human brain through behavioral, anatomical, and physiological studies in nonhuman primates. The main focus is on the principal sulcus (PS) (Walkers'area 46) of the macaque dorsolateral prefrontal cortex; this region of the primate cortex is essential for the process of working memory, which underlies a wide range of cognitive processes in humans including comprehension, reasoning, and planning for the future. The specific plan for the next five years is to continue neurobiological studies of the spatial memory functions of the PS at the areal, network, column and single cell levels. A series of anatomical studies will combine pathway tracing and electrophysiology and, in some instances immunocytochemistry, to examine selected visual, motor and intrinsic connections of prefrontal columns upon which memory functions are mapped (Specific Aim #1). In complementary studies, a battery of functional approaches, e.g., intracortical injections of bicucculine for temporary disruption of function (Specific Aim #2), single- and double-label 2-deoxyglucose (Specific Aims #3 and #4) and finally single cell recording studies (Specific Aim #5) will be conducted in animals trained to perform memory-guided and sensory-guided oculomotor delayed response tasks. These studies are designed to provide a comprehensive analysis of the topography and dynamics of working memory in prefrontal cortex and a test of the hypothesis that areas anatomically interconnected with the PS are dedicated to spatial cognition, each making a distinctive contribution. In addition, the RSA supported studies on nonhuman primates have implications for understanding the causes and symptoms of schizophrenia, the mental disease in which frontal lobe dysfunction is most prominent. Through my role as P.I.. of an NIMH funded Center for Neuroscience Research in Schizophrenia, I will be engaged directly in immunocytochemical, cytological, and receptor autoradiographic studies of schizophrenic cortex and, in general, the Center will develop primate models by manipulating cortical development in utero and also by lesion and drug induction of symptoms such as deficits in predictive eye tracking, memory and perseverative behavior. The proposed studies should advance our understanding of the circuit and cellular basis of cognitive functions, their development in ontogeny and their dissolution in mental disease.

This is a competing renewal to study the structure and function of the prefrontal cortex in nonhuman primates. The proposed research has the long- range goal of understanding cognitive processes in the human brain through animal models. Its focus is on the principal sulcus (PS) (Walkers'area 46) of the macaque dorsolateral prefrontal cortex; this region of the primate cortex is essential for the process of working memory. Our specific goal in this grant is to provide a neurobiological foundation for understanding the memory functions of the PS at the areal, network, column and single cell levels. A series of anatomical studies will combine pathway tracing and electrophysiology and, in some instances immunocytochemistry, to examine selected visual, motor and intrinsic connections of prefrontal columns upon which memory functions are mapped. In complementary studies, a battery of functional approaches, e.g. intracortical injections of bicucculine for temporary disruption of function (Specific Aim #2), single- and double-label 2-deoxyglucose (Specific Aims #3 and #4) and finally single cell recording studies (Specific Aim #5) conducted in animals trained to perform memory-guided and sensory-guided oculomotor delayed response tasks are designed to provide a comprehensive analysis of the topography and dynamics of working memory in prefrontal cortex. These studies will also test the hypothesis that areas anatomically interconnected with the PS and parietal cortex are likewise dedicated to spatial cognition, each making a distinctive contribution within a distributed network defined by circuitry. The 2-deoxyglucose metabolic mapping technique allows visualization of metabolic activity in all areas of the brain during a given behavioral condition; and the double-label version of this method, developed in this laboratory, can address the long-standing issue of the cortical column as the functional unit of the cerebral cortex by examining the same cortical columns under two behavioral conditions in the very same animal. The columnar basis of working memory at the cellular level will be addressed by combined anatomical tracing and single cell recording studies. The proposed studies should advance our understanding of the circuit and cellular basis of cognitive functions and their breakdown in mental disease.

This request for renewal of an RSA is based on a continuing commitment to enhance understanding of cognitive processes in the human brain through behavioral, anatomical, and physiological research in nonhuman primates. The main focus of this research program is on the structural and physiological mechanisms of the prefrontal cortex (PFC), the area shown in numerous clinical and experimental studies to be essential for the cognitive processes of comprehension, reasoning, and intentionality. I plan to pursue the several avenues of research already opened by our current studies on working memory at the areal, circuit, cellular and synaptic levels of analysis. Specific issues explore: (1) the domain specificity of visual memory circuits and memory modules within the PFC; (2) the localization and mechanisms of auditory working memory systems; (3) the organization of these levels in relation to motor systems; (4) the maintenance of the memory trace, the source of pre- and post-response signals and the interactions between PFC and other regions of the brain; and (5) the elucidation of working memory domains in humans. As in the past, these aims will be accomplished through a multidisciplinary research strategy. Functional analyses rely on single cell recording and 2- deoxyglucose metabolic labeling in conjunction with a variety of precisely controlled sensory-guided and memory-guided behavioral paradigms. The analyses are supported by detailed knowledge of the local and long-tract connections and synaptic architecture of prefrontal circuits. Advanced tracing with PHA-L, biotinylated PHA-L and dextrans and/or fluorescent dyes combined with immunocytochemical methodology will be employed in vivo and in fixed tissue slices and subjected to analysis at both the light and electronmicroscopic analyses. Overall, the proposed research effort is expected to illuminate the structure and function of the prefrontal cortex and advance our understanding of the neurobiological basis of normal and disordered cognition.

This is a competing renewal to study the structure and function of the prefrontal cortex in nonhuman primates. The proposed research has the long- range goal of understanding cognitive processes in the human brain through animal models. Its focus is on the principal sulcus (PS) (Walkers'area 46) of the macaque dorsolateral prefrontal cortex; this region of the primate cortex is essential for the process of working memory. Our specific goal in this grant is to provide a neurobiological foundation for understanding the memory functions of the PS at the areal, network, column and single cell levels. A series of anatomical studies will combine pathway tracing and electrophysiology and, in some instances immunocytochemistry, to examine selected visual, motor and intrinsic connections of prefrontal columns upon which memory functions are mapped. In complementary studies, a battery of functional approaches, e.g. intracortical injections of bicucculine for temporary disruption of function (Specific Aim #2), single- and double-label 2-deoxyglucose (Specific Aims #3 and #4) and finally single cell recording studies (Specific Aim #5) conducted in animals trained to perform memory-guided and sensory-guided oculomotor delayed response tasks are designed to provide a comprehensive analysis of the topography and dynamics of working memory in prefrontal cortex. These studies will also test the hypothesis that areas anatomically interconnected with the PS and parietal cortex are likewise dedicated to spatial cognition, each making a distinctive contribution within a distributed network defined by circuitry. The 2-deoxyglucose metabolic mapping technique allows visualization of metabolic activity in all areas of the brain during a given behavioral condition; and the double-label version of this method, developed in this laboratory, can address the long-standing issue of the cortical column as the functional unit of the cerebral cortex by examining the same cortical columns under two behavioral conditions in the very same animal. The columnar basis of working memory at the cellular level will be addressed by combined anatomical tracing and single cell recording studies. The proposed studies should advance our understanding of the circuit and cellular basis of cognitive functions and their breakdown in mental disease.

This is a response to a NIDA RFA for the establishment of a Neuroscience Network. This proposal contains a series of highly interdigitated projects, connected both scientifically and technically. The major theme running through all four projects is the action of neurotrophic factors and cytokines in neural systems relevant to drug abuse. A second major theme running through three of the four projects is modulation of mesolimbic dopamine systems by neurotransmitters and trophic factors. A third theme binding two of the projects closely together is the study of cholinergic-dopaminergic interactions. The Network involves entirely new project from two labs already involved in drug abuse research and recruits the laboratories of two well established neuroscientists to drug abuse research for the first time. A major connection of all the investigators is their commitment to the use of molecular and cellular tools in the service of understanding brain and behavior. The investigators, who comprise a highly collegial group, well known to each other, are particularly enthusiastic about the communications core which will facilitate their work together. This RFA has provided an opportunity for the group to develop synergistic interactions across physical distance that will speed their investigations of fundamental processes in the nervous system relevant to the actions of drugs of abuse.

The long range objective of this laboratory is to understand the cellular and circuit basis of cognitive operations of the prefrontal cortex, the brain area closely associated with the executive functions of the human brain. In the past cycle of this grant, we have defined separate spatial and nonspatial visual processing domains associated with the dorsolateral and inferior prefrontal convexities, respectively. The goal of the present application is to functionally and anatomically dissect the intrinsic circuit mechanisms by which the prefrontal cortex performs its basic cognitive operations and to test the hypothesis that the prefrontal cortex is composed of content- constrained modules not only at the level of cytoarchitectonic areas (macroarchitecture) but also at the level of columns and microcolumns (microarchitecture). In Specific Aim number 1, powerful new multielectrode technology will be applied in vivo to the study of the dorsolateral prefrontal cortex to examine the dynamic interactions of ensembles of neurons with cue, delay and action-related response properties within and across cortical columns during spatial working memory tasks. This method will also allow analysis of the contributions of fast-spiking (putative interneurons) and regular spiking (putative pyramidal) neurons to these dynamic interactions and spatial memory field formation in the dorsolateral cortex. In Specific Aim number 2, the same powerful method will be applied to the object processing system of the inferior prefrontal cortex (IFC) to assess ensemble encoding in relation to the object/face response properties of IFC neurons. Specific Aim number 3 will complement the in vivo approach by employing whole cell patch clamp recording combined with infrared microscopy to visualize and directly study local circuits among functionally connected neurons in cortical slices. Collectively, these aims will explore a new level of functional anatomy in prefrontal cortex with the goal of providing mechanistic explanations of cognitive phenomena and insight into pathological processes of mental illness.

This two-day workshop will define particular opportunities in the field of cognitive neuroscience. It is unique in its intent to explicitly identify particular linkages to promote among cognition, computation and biology. The three organizers are highly regarded leaders in their fields, and the speakers include a diverse group with many well-recognized names. Topics include how to define cognitive neuroscience and how to use biological, behavioral and computational approaches to study cognition, and the format provides adequate time to discuss the several topics proposed.
Results from the workshop will include a set of recommendations to NSF for programmatic and cross-directorate activity mechanisms to encourage productive new approaches to cognitive neuroscience.